Unlike infections encountered in medicine, surgical infections are generally caused by mixed species of aerobic and anaerobic bacteria, and they occur at sites previously injured by disease or trauma containing necrotic or damaged tissue favorable for the growth of anaerobic organisms. In intraabdominal sepsis the most common mixture includes an enteric Gram negative facultative aerobe (typically E. coli), Gram negative anaerobes (typically B. fragilis) and mixed Gram positive cocci, both aerobes an anaerobes. The pathogenicity of B. fragilis has frequently been questioned and only recently has evidence been gained that B. fragilis can cause abscesses in normal hosts. We have developed an animal model proving that B. fragilis can increase the lethality of an otherwise non-lethal E. coli inoculum when both microbes are trapped together in a fibrin mesh implanted into the peritoneal cavity. The present proposal has two aims: 1) to determine those characteristics of the Bacteroides organism which are responsible for synergy with E. coli in vivo. 2) to determine the mechanism by which Bacteroides impairs host defenses. For Aim 1, we plan to test a variety of Bacteroides strains for their capacity to synergize with E. coli. The Bacteroides strains vary with respect to the amount and morphology of the capsule produced, the metabolic products produced, and resistance to phagocytosis. Based on these results, various bacterial products, i.e., capsule, bacterial enzymes, products of interaction with various organic substrates, and bacterial by-products will be tested when incorporated with E. coli within the intraperitoneal fibrin clot. This will permit us to determine whether nonviable components of the B. fragilis organism are capable of increasing the virulence of E. coli infections in this model. The second aim is related intimately to the first: we will determine how those Bacteroides products which are responsible for synergism in vivo, also impair human leukocyte function and complement activity in vitro. The human leukocyte functions to be studied are motility, chemotaxis, chemiluminescence, phagocytosis and bacterial killing. It should thus be possible to obtain parallel in vivo and in vitro data which will provide a clearer understanding of the mechanism by which Bacteroides strains may impair host defenses and thereby foster lethal sepsis under conditions which simulate complex surgical infection.